Alkene, alkyne or cycloalkylene derivatives

ABSTRACT

A compound of the formula ##STR1## wherein X has the formula --CR 5  ═CR 6  --, --C.tbd.C-- or ##STR2## wherein ring A is phenyl, naphthyl or heterocyclic; wherein R 1  is hydrogen, alkyl, alkanoyl or aroyl; 
     wherein R 2 , R 3  and R 4 , which may be the same or different, each is an electron withdrawing substituent of each is hydrogen or alkyl, alkoxy or dialkylamino, provided that when ring A is phenyl or naphthyl at least one of R 2 , R 3  and R 4  is an electron-withdrawing substitutent; 
     wherein R 5  and R 6 , each is hydrogen, halogeno or alkyl; 
     wherein R 7  is alkyl or halogenoalkyl; and wherein R 8  has the formula --Y--Q--R 9  wherein Y is straight- or branched-chain alkylene or alkenylene; wherein Q is --O--, --S--, --SO-- or --SO 2  --; and 
     wherein R 9  is alkyl or up to 6 carbon atoms which contains one or more defined substituents, processes for their manufacture and pharmaceutical compositions containing them. The compounds possess antiandrogenic activity and may be used in the treatment of androgen-dependent disease conditions such as prostatic disease, acne, hirsutism or seborrhoea.

This invention relates to novel alkene, alkyne or cycloalkylenederivatives which possess antiandrogenic properties.

Various 4-arylbut-3-en-2-ol derivatives of the general formula: ##STR3##wherein Ar is a phenyl group bearing one or more electron-withdrawingsubstituents, are known, for a variety of purposes. For example, suchcompounds wherein R⁷ is t-butyl and R⁸ is imidazol-1-ylmethyl or1,2,4-triazol-1-ylmethyl are known, from European Patent SpecificationsNos 40345 and 52424 and other related specifications, as plant growthregulators or fungicides. When R⁷ and R⁸ are both methyl the compoundwherein Ar is 3-nitrophenyl is known from U.S. Pat. No. 4139561, and thecompound wherein Ar is 4-chlorophenyl is known from Synthesis, 1980,pages 815-816, in both cases the compounds being used as chemicalintermediates. When R⁷ is methyl, R⁸ is carboxymethyl orethoxycarbonylmethyl and Ar is 4-chlorophenyl, the compounds aredescribed in Biochemistry, 1964, Volume 3, pages 1998 et seq., aspotential (although inactive) inhibitors of cholesterol biosynthesis.

Various acylanilides of the general formula ##STR4## are known asantiandrogens. The compounds wherein R⁷ and R⁸ are both methyl and Ar is4-nitro-3-trifluorophenyl is known as hydroxyflutamide, and is believedto be the active metabolite of the commercially-available antiandrogenFLUTAMIDE. Other acylanilides which possess antiandrogenic activity areknown from European Specifications Nos 2309, 2892 and 40932, and fromJapanese Specification No. 52-128329.

According to the present invention there is provided a compound of theformula ##STR5## wherein X has the formula ##STR6## wherein ring A isphenyl, naphthyl or heterocyclic; wherein R¹ is hydrogen, alkyl oralkanoyl each of up to 6 carbon atoms or aroyl of up to 10 carbon atoms;wherein R², R³ and R⁴, which may be the same or different, each is anelectron withdrawing substituent selected from halogeno, nitro, cyanoand trifluoromethyl, and alkylthio, alkylsulphinyl and alkylsulphonyleach of up to 6 carbon atoms, or each is hydrogen or alkyl, alkoxy ordialkylamino each of up to 6 carbon atoms, provided that when ring A isphenyl or naphthyl at least one of R², R³ and R⁴ is anelectron-withdrawing substituent;

wherein R⁵ and R⁶, which may be the same or different, each is hydrogen,halogeno or alkyl of up to 6 carbon atoms;

wherein R⁷ is alkyl or halogenoalkyl each of up to 6 carbon atoms; andwherein R⁸ has the formula

    --Y--Q--R.sup.9

wherein Y is straight- or branched-chain alkylene or alkenylene each ofup to 6 carbon atoms; wherein Q is --O--, --S--, --SO-- or --SO₂ --; and

wherein R⁹ is alkyl of up to 6 carbon atoms which contains one or moresubstituents selected from halogeno, cyano, hydroxy, amino,hydroxyimino, guanidino, ureido and carbamoyl;

alkoxy, alkylamino, alkylthio, alkylsulphinyl, alkylsulphonyl,alkylcarbamoyl, alkoxyimino, alkanoyl, halogenoalkanoyl, alkanoylaminoand alkylsulphonamido each of up to 6 carbon atoms;

alkoxyalkoxy, dialkylamino and dialkylcarbamoyl each of up to 12 carbonatoms;

aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl, aryloxyimino andaroyl each of up to 10 carbon atoms; heterocyclyl, heterocyclylthio,heterocyclylsulphinyl, heterocyclylsulphonyl, heterocyclyloxyimino andheterocyclylcarbonyl;

and alkylenedioxy of to 2 to 4 carbon atoms wherein both oxygen atomsare attached to the same carbon atom of R⁹.

It will be observed that a compound of the invention wherein X is otherthan ethynylene may exist in two geometrical isomeric forms dependingupon the disposition of the various substituents about the olefinic orcycloalkyl bond --X--, and also that a compound of the inventionpossesses at least one asymmetric carbon atom, namely the carbon atomwhich bears the substituents R⁷, R⁸ and --OR¹, and it can thereforeexist in racemic and optically-active forms. It is to be understood thatthis invention encompasses either geometric isomer in racemic form, andany optically-active form of the compound which possesses antiandrogenicactivity, it being a matter of common general knowledge how a racemiccompound may be resolved into its optically-active forms and how anyantiandrogenic activity present in any of these forms may be determined.

A suitable value for ring A when it is heterocyclyl, or for theheterocyclyl, heterocyclylthio-, sulphinyl- or sulphonyl-,heterocyclyloxyimino or heterocyclylcarbonyl substituent in R⁹ is, forexample, a 5- or 6-membered saturated or unsaturated heterocyclic whichcontains one, two or three hetero atoms selected from oxygen, nitrogenand sulphur, which heterocyclic is a single ring or is fused to one ortwo benzo-rings or to another heterocyclic ring as defined above, andwhich heterocyclic is unsubstituted or bears substituents R², R³ and R⁴as defined above, or when a substitutent in R⁹ may also bear one or morehydroxy, mercapto or amino substituents.

Ring A when heterocyclic is preferably pyridyl, quinolyl or thienylwhich is unsubstituted or bears one or two halogeno or cyanosubstituents, or one nitro substituent.

When R⁹ is alkyl bearing a heterocyclyl containing substituent theheterocyclyl group is preferably furyl, thienyl, pyridyl, quinolyl,pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, triazolyl, purinyl,1,4-benzodioxanyl, pyrazolo-pyrimidinyl or acridinyl which isunsubstituted or bears one or more substituents selected from halogeno,trifluoromethyl, hydroxy, mercapto and amino, and alkyl and alkoxy eachof up to 6 carbon atoms.

A suitable value for R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ when it is alkyl is,for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or n-hexyl.

A suitable value for R¹ when it is alkanoyl, or for the alkanoylsubstituent in R⁹ when R⁹ is alkyl substituted by alkanoyl is, forexample, formyl, acetyl or propionyl.

A suitable value for R¹ when it is aroyl, or for the aroyl substituentin R9 when R9 is alkyl substituted by aroyl, is, for example, benzoyl,p-fluorobenzoyl or p-toluoyl.

A suitable value for R², R³, R⁴, R⁵ or R⁶ when it is halogeno, or forthe halogeno substituent in R⁷ or R⁹ is, for example, fluoro, chloro orbromo.

A suitable value for R², R³ or R⁴ when it is alkoxy, or for the alkoxysubstituent in R⁹ when R⁹ is alkyl substituted by alkoxy is, forexample, methoxy or ethoxy.

A suitable value for R², R³ or R⁴ when it is alkylthio, alkylsulphinylor alkylsulphonyl, or for the alkylthio, alkylsulphinyl oralkylsulphonyl substituent in R⁹ when R⁹ is alkyl substituted byalkylthio, alkylsulphinyl or alkylsulphonyl is, for example, methylthio,ethylthio, n-propylthio, methylsulphinyl, ethylsulphinyl,n-propylsulphinyl, methylsulphonyl, ethylsulphonyl or n-propylsulphonyl.

A suitable value for R², R³ or R⁴ when it is dialkylamino, or for thedialkylamino substituent in R⁹ when R⁹ is alkyl substituted bydialkylamino is, for example, dimethylamino or diethylamino.

A suitable value for R⁷ when it is halogenoalkyl is, for example,trifluoromethyl, pentafluoroethyl, heptafluoropropyl, chloromethyl ordichloromethyl.

A suitable value for the alkanoylamino, alkylsulphonamido, alkylamino,alkylcarbamoyl, dialkylcarbamoyl, alkoxyimino, halogenoalkanoyl oralkoxyalkoxy substituent in R⁹ when R⁹ is alkyl which bears such asubstituent is, for example, acetamido, methylsulphonamido, methylamino,ethylamino, methylcarbamoyl, dimethylcarbamoyl, methoxyimino,chloroacetyl or methoxyethoxy.

A suitable value for the aryl, aryloxy, arylthio, arylsulphinyl,arylsulphonyl or aryloxyimino substituent in R⁹ when R⁹ is alkyl whichbears such a substituent is, for example, phenyl, naphthyl, tolyl,fluorophenyl, chlorophenyl, methoxyphenyl, nitrophenyl,methylthiophenyl, methylsulphonylphenyl, carbamoylphenyl,acetamidophenyl or dimethylaminophenyl, or the corresponding phenoxy,phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxyimino orsubstituted phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl orphenoxyimino.

A preferred compound of the invention has the formula stated abovewherein X is --CR⁵ ═CR⁶ --, in the trans-configuration, wherein ring Ais phenyl, wherein one or two (the same or different) of R², R³ and R⁴are fluoro, chloro, cyano, trifluoromethyl or nitro, the others of R²,R³ and R⁴ being hydrogen, wherein R¹, R⁵ and R⁶ are all hydrogen,wherein R⁷ is trifluoromethyl, pentafluoroethyl, heptafluoropropyl,chloromethyl or dichloromethyl; wherein Q is --S, --SO-- or --SO₂,wherein Y is --CH₂ -- and wherein R⁹ is straight-chain-alkyl of up to 4carbon atoms which bears one or two substituents selected from chloro,cyano, hydroxy, amino, carbamoyl, methoxy, ethoxy, methylthio,methylsulphonyl, acetyl, acetamido, ureido, dimethylamino,dimethylcarbamoyl, phenyl, fluorophenyl, methylthiophenyl,methylsulphonylphenyl, naphthyl, methoxyphenoxy, phenylthio,methylthiophenylthio, methylsulphonylphenylthio, benzoyl, thenoyl,furyl, pyridyl, pyrazinyl, methylthiazolyl and 1,4-benzodioxanyl; orwhich bears one such substituent and also three fluorine substituents onthe terminal carbon atom; or which bers an ethylenedioxy ortrimethylene-1,3-dioxy substituent; or which bears three fluorinesubstituents on the terminal crbon atom.

A particularly preferred compound of the invention is one defined in thelast paragraph above wherein ring A is 3,4-dichlorophenyl,3-chloro-4-cyanophenyl, 4-cyano-3-trifluoromethylphenyl or4-fluoro-3-trifluoromethylphenyl and wherein R⁷ is trifluoromethyl.

Specific compounds of the invention are hereinafter described in theExamples. Of these, preferred compounds by virtue of their high level ofantiandrogenic acitvity are:

1-(3-methoxypropylthio)-, 1-(3-hydroxybutylthio)-,1-(2-hydroxypropylthio)-, 1-[3,3-(trimethylene-1,3-dioxy)propylthio]-,1-(2-furylmethylthio)-, 1-(3-oxobutylthio)-,1-(3,3-ethylenedioxybutylthio)-, 1-(3-hydroxypropylthio)-,1-(2,3-dihydroxypropylthio-), 1-(2,3-dimethoxypropylthio)-,1-benzylthio-, 1-(3-phenylpropylthio)-, 1-m-fluorobenzylthio-,1-p-fluorobenzylthio-, 1-(3-p-methoxyphenylpropylthio)-,1-(2-carbamoylethylthio)-, 1-(2-N,N-dimethylcarbamoylethylthio)-,1-(pyrid-3-ylmethylthio)-, 1-(2-methylthiazol-4-ylmethylthio)-,1-(3-phenoxypropylthio)-, 1-(4-oxo-4-phenylbutylthio)-,1-[4-oxo-4-(thien-2-yl)butylthio]-, 1-(3-hydroxy-3-phenylpropylthio)-,1-(3-p-fluorophenyl-3-fluorophenyl-3-hydroxypropylthio)-,1-(3-hydroxy-3-p-methylthiophenylpropylthio)-,1-(3-hydroxy-3-p-methylsulphonylphenylpropylthio- and1-(3-hydroxy-3-p-methoxyphenylpropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol;

1-(2-carbamoylethylthio)-, 1-(p-methylsulphonylbenzylthio)- and1-(3-methoxypropylthio)-4-(3-chloro-4-cyanophenyl)-2-trifluoromethylbut-trans-3-en-2-ol;and

1-(3-methylsulphonylpropylsulphonyl)-4-(3,4-dichlorophenyl)-2-trifluoromethylbut-trans-3-en-2-ol.

A compound of the invention may be manufactured by any chemical processknown to be suitable for the manufacture of chemically-analogouscompounds.

One process for the manufacture of an alkene of the invention wherein R¹is hydroxy and X is --CR⁵ ═CR⁶ -- comprises the reaction of a compoundof the formula: ##STR7## wherein A, R², R³, R⁴, R⁵, R⁶ and R⁷ have themeanings stated above, with an organometallic compound of the formula R⁸-M, wherein R⁸ has the meaning stated above and M is a metallic group.

M may be, for example, lithium, and the reaction is preferably carriedout in an inert diluent or solvent, for example tetrahydrofuran, at areduced temperature, for example at -70° C. to -80° C.

The starting material for the abovementioned reaction may be obtained bythe reaction of an aldehyde or ketone of the formula: ##STR8## whereinA, R², R³, R⁴ and R⁵ have the meanings stated above, with a compound ofthe formula

    R.sup.6 CH.sub.2 COR.sup.7 or (Ph).sub.3 P═CR.sup.6 COR.sup.7 or ##STR9## wherein R.sup.6 and R.sup.7 have the meanings stated above.

An alternative process for the manufacture of an alkene of the inventionwherein R¹ is hydroxy, X is --CR⁵ ═CR⁶ --, and Y is --CH₂ -- comprisesthe reaction of an epoxide of the formula: ##STR10## wherein A, R², R³,R⁴, R⁵, R⁶ and R⁷ have the meanings stated above, with a compound of theformula R⁹ --Q--H, wherein R⁹ and Q have the meanings stated above or,when Q is --S--, with the corresponding isothiouronium salt of theformula ##STR11## B.sup.⊖ wherein B.sup.⊖ is an anion, for example thechloride, bromide or tosylate ion.

The abovementioned reaction is particularly suitable for the manufactureof an alkene of the invention wherein Q is --S-- or wherein the --H atomis otherwise reactive. The reaction is conveniently carried out atlaboratory temperature in an inert diluent or solvent, for exampletetrahydrofuran or diethyl ether, or, when isothiouronium salt is usedin tetrahydrofuran in the presence of an aqueous base, for examplesodium hydroxide solution.

The epoxide starting material may be obtained by the reaction of acompound of the formula: ##STR12## (the preparation of which isdescribed above) with trimethylsulphoxonium iodide in the presence of abase, for example butyl-lithium or, under phase transfer conditions, analkali metal hydroxide.

A process for the manufacture of a cycloalkylene derivative of theinvention wherein X is ##STR13## comprises the reaction of a compound ofthe formula ##STR14## wherein A, R², R³, R⁴, R⁵, R⁶ and M have themeanings stated above, with a compound of the formula

    R.sup.7 COR.sup.8

wherein R⁷ and R⁸ have the meanings stated above.

This reaction may be carried out at a low temperature in an inertdiluent or solvent. M is preferably lithium.

A process for the manufacture of an alkyne of the invention wherein X is--C.tbd.C-- comprises the reaction of a compound of the formula##STR15## wherein A, R¹, R², R³ and R⁴ have the meanings stated aboveand wherein Z is a displaceable group, with a compound of the formula

    HC.tbd.C--CR.sup.7 R.sup.8 OR.sup.1

wherein R¹, R⁷ and R⁸ have the meanings stated above.

A suitable value for Z is, for example, an iodo group.

A compound of the invention wherein X is --C.tbd.C-- may be reduced tothe corresponding compound of the invention wherein X is --CH═CH--.Conventional conditions for the reduction may be chosen so that eitherthe cis- or trans-alkene is obtained.

Various interconversions of compounds of the invention wherein R⁹ hasdifferent meanings are possible. Thus, for example (i) a compoundwherein R⁹ bears an amino substituent may be acylated to give thecorresponding compound wherein R⁹ bears an alkanoylamino,alkoxycarbonylamino or alkylsulphonamido substituent; (ii) a compoundwherein R⁹ is alkyl substituted by alkanoyl may be reduced to thecorresponding compound wherein R⁹ is hydroxyalkyl.

A compound of the invention wherein R¹ is alkyl may be prepared by thealkylation of the corresponding compound wherein R¹ is hydrogen.

A compound of the invention wherein R¹ is alkanoyl or aroyl may beprepared by the acylation of the corresponding compound wherein R¹ ishydrogen.

A compound of the invention wherein one or more of R², R³, R⁴ and asubstituent in R⁹ is alkylsulphinyl or alkylsulphonyl, or a substituentin R⁹ is arylsulphinyl, arylsulphonyl, heterocyclylsulphinyl orheterocyclylsulphonyl, or Q is --SO-- or --SO₂ --, may be prepared bythe oxidation of the corresponding compound wherein one or more of R²,R³, and R⁴ and a substituent in R⁹ is alkylthio, arylthio orheterocyclylthio, or Q is --S--, respectively. The oxidising agent andconditions used will determine whether a sulphinyl or a sulphonylcompound is obtained. Thus, oxidation with sodium metaperiodate inmethanol solution at or below laboratory temperature will generallyconvert a thio compound into the corresponding sulphinyl compound; andoxidation with hydrogen peroxide in acetic acid solution or with apersulphate in aqueous solution at or above laboratory temperature, willgenerally convert a thio compound into the corresponding sulphonylcompound, although this reaction occasionally stops at the sulphinylstage.

As stated above, a compound of the invention possesses antiandrogenicproperties as demonstrated by its ability to decrease the weight of theseminal vesicles of a castrated male rat when administered concurrentlywith testosterone propionate. A compound of the invention may thereforebe used in the treatment of, for example, malignant or benign prostaticdisease or of androgen dependent disease conditions, such as acne,hirsutism or seborrhoea, in warm-blooded vertebrates including man. Itmay also be used to improve ovulation in a domestic animal.

At a dose of a compound of the invention which produces antiandrogenicactivity in rats no symptom of toxicity is apparent.

The compound of the invention may be administered to a warm-bloodedanimal in the form of a pharmaceutical or veterinary composition whichcomprises the compound in association with a pharmaceutically-acceptablediluent or carrier.

The composition may be in a form suitable for oral dosage, as a tablet,capsule, aqueous or oily solution or suspension, or emulsion. It mayalternatively be in the form of a sterile solution or suspensionsuitable for parenteral administration, or be in the form of an ointmentor lotion for topical administration, or be in the form of asuppository.

The composition may additionally contain one or more drugs selected fromanti-oestrogens, for example tamoxifen; aromatase inhibitors, forexample testolactone or aminoglutethimide; progestins, for examplemedroxyprogesterone acetate; inhibitors of gonadotrophin secretion, forexample danazol; LH-RH analogues, for example buserelin; cytotoxicagents, for example cyclophosphamide; antibiotics, for examplepenicillin or oxytetracyclin; and anti-inflammatory agents, for example,especially for topical use, fluocinolone acetonide.

The compound of the invention will normally be administered to awarm-blooded animal at a dose of between 0.1 mg. and 125 mg. per kg.bodyweight.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1

A solution of4-(3,4-dichlorophenyl)-1,2-epoxy-2-trifluoromethylbut-trans-3-ene (0.3g.) in tetrahydrofuran (5 ml.) was added dropwise to a stirred mixtureof 2-methylthioethanethiol (0.2 g.) and sodium hydride (0.08 g. of a 50%dispersion in mineral oil) in tetrahydrofuran (25 ml.) and the mixturewas stirred at laboratory temperature for 1.5 hours and then poured intowater. The mixture was extracted with ethyl acetate and the extract waswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulphate and evaporated to dryness under reduced pressure. Theresidue was purified by chromatography on a silica gel column using a3:2 v/v mixture of petroleum ether (b.p. 60°-80° C.) and methylenechloride as eluant. There was thus obtained as an oil4-(3,4-dichlorophenyl)-1-[(2-methylthioethyl)thio]-2-trifluoromethylbut-trans-3-en-2-ol,m.p. 64° C.

The epoxybutene used as starting material was obtained as follows:

A solution of 3,4-dichlorobenzaldehyde (10 g.) in ethanol (50 ml.), andthen 1,1,1-trifluoroacetone (6.5 ml.), were successively added to astirred suspension of freshly ground lithium hydroxide monohydrate (1.0g.) in ethanol (100 ml.), the trifluoroacetone being added by injectionbelow the surface of the reaction mixture, and the mixture was stirredfor 1 hour and then poured into water (600 ml.). The mixture wasextracted with ethyl acetate and the extract was washed with aqueous2N-hydrochloric acid and then saturated aqueous sodium chloridesolution, dried over magnesium sulphate and evaporated to dryness underreduced pressure. The residue was purified by chromatography on a silicagel column using a 7:3 v/v mixture of petroleum ether (b.p. 60°-80° C.)and methylene chloride as eluant. There was thus obtained1,1,1-trifluoro-4-(3,4-dichlorophenyl)but-trans-3-en-2-one, m.p. 81° C.

n-Butyl-lithium (11.6 ml. of a 1.6 molar solution in hexane) was addeddropwise to a stirred suspension of trimethylsulphoxonium iodide (4.1g.) in tetrahydrofuran (200 ml.) which was cooled to -10° C., and themixture was stirred at that temperature for 2 hours and then added to astirred solution of4-(3,4-dichlorophenyl)-1,1,1-trifluorobut-trans-3-en-2-one (2.0 g.) intetrahydrofuran (100 ml.). The mixture was stirred for 90 minutes,saturated aqueous ammonium chloride solution (75 ml.) was added and themixture was partitioned between water and ethyl acetate. The layers wereseparated, the aqueous layer was extracted with ethyl acetate and thecombined ethyl acetate solutions were washed with saturated aqueoussodium chloride solution, dried over magnesium sulphate and evaporatedto dryness under reduced pressure. The residue was purified bychromatography on a silica gel column using a 4:1 v/v mixture ofpetroleum ether (b.p. 60°-80° C.) and methylene chloride as eluant.There was thus obtained as an oil 4-(3,4-dichlorophenyl)-1,2-epoxy-2-trifluoromethyl-but-trans-3-ene.

The process described above was repeated using the appropriate thiol andthe appropriate epoxide, prepared from the appropriate butenone eitheras described above or by the method generally described in AngewandteChemie (International Edition), 1973, Volume 12, page 845. There werethus obtained the compounds described in the following table:

    ______________________________________                                         ##STR16##                                                                    R.sup.3                                                                             R.sup.4                                                                              R.sup.9            m.p. (°C.)                                                                     Note                                  ______________________________________                                        Cl    Cl     CH.sub.2 CHOHCH.sub.2 OH                                                                         (oil)                                         CF.sub.3                                                                            CN     CH.sub.2 CHOHCH.sub.2 OH                                                                         (oil)   1                                     Cl    Cl     (CH.sub.2).sub.2 CHOHCH.sub.3                                                                    (oil)                                         CF.sub.3                                                                            CN     (CH.sub.2).sub.2 CHOHCH.sub.3                                                                    (oil)   1                                     Cl    Cl     (CH.sub.2).sub.2 OH                                                                              112-113                                       CF.sub.3                                                                            CN     (CH.sub.2).sub.2 OH                                                                              (oil)   1                                     Cl    Cl     CH.sub.2 CHOHCF.sub.3                                                                            (oil)                                         CF.sub.3                                                                            CN     CH.sub.2 CHOHCF.sub.3                                                                            (oil)   1                                     Cl    Cl     CH.sub.2 CHOHCH.sub.3                                                                            (oil)                                         CF.sub.3                                                                            CN     CH.sub.2 CHOHCH.sub.3                                                                            (oil)   1                                     CF.sub.3                                                                            CN                                                                                    ##STR17##         (oil)   1                                     Cl    Cl                                                                                    ##STR18##         (oil)                                         CF.sub.3                                                                            CN                                                                                    ##STR19##         (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.2 COCH.sub.3                                                                      (oil)   1                                     Cl    Cl     (CH.sub.2).sub.2 COCH.sub.3                                                                      (oil)                                         Cl    Cl     (CH.sub.2).sub.2 CONH.sub.2                                                                      76                                            Cl    CN     (CH.sub.2).sub.2 CONH.sub.2                                                                      (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.2 CONH.sub.2                                                                      (oil)   1                                     Cl    CN     (CH.sub.2).sub.2 OCH.sub.3                                                                       54-55   1                                     Cl    Cl     (CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                               (oil)                                         Cl    CN     (CH.sub.2).sub.2 SCH.sub.3                                                                       (oil)   1                                     Cl    Cl     (CH.sub.2).sub.3 SCH.sub.3                                                                       (oil)                                         Cl    CN     (CH.sub.2).sub.3 SCH.sub.3                                                                       (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.3 SCH.sub.3                                                                       (oil)   1                                     Cl    CN     (CH.sub.2).sub.2 NHCOCH.sub.3                                                                    (oil)   1                                     Cl    Cl     (CH.sub.2).sub.2 NHCONH.sub.2                                                                    118-130                                       Cl    Cl     CH.sub.2 C.sub.6 H.sub.5                                                                         (oil)                                         CF.sub.3                                                                            CN     CH.sub.2 C.sub.6 H.sub.5                                                                         80-84                                         Cl    Cl     (CH.sub.2).sub.24-fluorophenyl                                                                   (oil)                                         Cl    Cl     CH.sub.21-naphthyl (oil)                                         Cl    Cl     CH.sub.22-furyl    (oil)                                         CF.sub.3                                                                            CN     CH.sub.22-furyl    (oil)   1                                     Cl    Cl     (CH.sub. 2).sub.2 NH.sub.2                                                                       137-138                                       Cl    Cl     (CH.sub.2).sub.22-pyrazinyl                                                                      (oil)                                         CF.sub.3                                                                            CN     (CH.sub.2).sub.22-pyrazinyl                                                                      (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.3 O4-methoxyphenyl                                                                (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.2 CON(CH.sub.3).sub.2                                                             (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.3 CON(CH.sub.3).sub.2                                                             (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                                 58-60   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.24-methylthiophenyl                                                               (oil)   1                                     CF.sub.3                                                                            CN     CH.sub.22-pyridyl  (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.22-pyridyl                                                                        (oil)   1                                     CF.sub.3                                                                            CN     CH.sub.2(1,4-benzodioxan-2-yl)                                                                   (oil)   1                                     CF.sub.3                                                                            CN     CH.sub.2 CHOHC.sub.6 H.sub.5                                                                     (oil)   1                                     CF.sub.3                                                                            CN     CH.sub.2 CHOH4-methyl-                                                                           (oil)   1                                                  sulphonylphenyl                                                  CF.sub.3                                                                            CN     CH.sub.2 CHOH3-pyridyl                                                                           (oil)   1                                     CF.sub.3                                                                            CN                                                                                    ##STR20##         (oil)   1                                     CF.sub.3                                                                            CN     (CH.sub.2).sub.2 CO4-fluorophenyl                                                                (oil)   2                                     ______________________________________                                    

Note 1 The butenone starting material was obtained by the reaction ofthe appropriate aldehyde with diethyl3,3,3-trifluoro-2-methyliminopropylphosphonate by the method describedin Tetrahedron Letters (1983), page 4229.4-(4-Cyano-3-trifluoromethylphenyl)-1,1,1-trifluorobut-3-en-2-one hasm.p. 119°-121° C. and4-(3-chloro-4-cyanophenyl)-1,1,1-trifluorobut-3-en-2-one has m.p.102°-104° C.

Note 2 Prepared by acid hydrolysis of the preceding compound.

EXAMPLE 2

A solution of sodium hydroxide (0.06 g.) in water (0.5 ml.) was addeddropwise to a stirred suspension of3-hydroxy-3-phenylpropylisothiouronium chloride (0.18 g.) intetrahydrofuran which was maintained at laboratory temperature under anatmosphere of argon, and the mixture was stirred for 15 minutes. Asolution of4-(4-cyano-3-trifluoromethylphenyl)-1,2-epoxy-2-trifluoromethylbut-trans-3-ene(0.205 g.) in tetrahydrofuran (2 ml.) was added and the mixture wasstirred at laboratory temperature for 20 hours, diluted with ethylacetate (20 ml.) and washed with saturated aqueous sodium chloridesolution (15 ml.). The organic solution was dried over magnesiumsulphate and evaporated to dryness and the residue was purified by flashchromatography on a silica gel (Merck 9385) column using a 2:1 v/vmixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate aseluent. There was thus obtained, as an oil,4-(4-cyano-3-trifluoromethylphenyl)-1-(3-hydroxy-3-phenylpropyl)thio-2-trifluoromethylbut-trans-3-en-2-ol.

The process described above was repeated using the appropriateisothiouronium chloride (or bromide indicated by an asterisk * in thetable, or tosylate, indicated by two asterisks ** in the table) and theappropriate epoxide as starting materials and there were thus obtainedthe compounds described in the following table:

    ______________________________________                                         ##STR21##                                                                    R.sup.3                                                                             R.sup.4                                                                              R.sup.9               m.p. (°C.)                          ______________________________________                                        Cl    Cl     (CH.sub.2).sub.3 CF.sub.3                                                                           (oil)                                      Cl    CN     (CH.sub.2).sub.3 CF.sub.3                                                                           (oil)                                      Cl    Cl     (CH.sub.2).sub.2 OCH.sub.3                                                                          (oil)                                      Cl    Cl     (CH.sub.2).sub.3 OCH.sub.3                                                                          (oil)                                      CF.sub.3                                                                            F      (CH.sub.2).sub.3 OCH.sub.3                                                                          (oil)                                      Cl    CN     (CH.sub.2).sub.3 OCH.sub.3                                                                          (oil)                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.3 OCH.sub.3                                                                          (oil)                                      Cl    CN     (CH.sub.2).sub.4 OCH.sub.3                                                                          (oil)                                      Cl    CN     (CH.sub.2).sub.3 OC.sub.2 H.sub.5                                                                   (oil)                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.3 OC.sub.2 H.sub.5                                                                   (oil)                                      Cl    Cl     (CH.sub.2).sub.2 CN   (oil)                                      Cl    Cl     (CH.sub.2).sub.3 CN   (oil)                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                                     (oil)*                                    CF.sub.3                                                                            CN     (CH.sub.2).sub.23-methylthiophenyl                                                                  (oil)                                      CF.sub.3                                                                            CN     CH.sub.23-methylsulphonylphenyl                                                                     (oil)                                      CF.sub.3                                                                            CN     CH.sub.24-methylsulphonylphenyl                                                                     (oil)                                      CF.sub.3                                                                            CN     CH.sub.24-fluorophenyl                                                                              (oil)                                      CF.sub.3                                                                            CN     CH.sub.23-pyridyl     (oil)                                      CF.sub.3                                                                            CN     CH.sub.24-pyridyl     133-134                                    CF.sub.3                                                                            CN     CH.sub.2(2-methylthiazol-4-yl)                                                                      (oil)                                      CF.sub.3                                                                            CN     CH.sub.2 CH(OCH.sub.3)CH.sub.2 OCH.sub.3                                                             (oil)**                                   CF.sub.3                                                                            CN     (CH.sub.2).sub.2 CHOH4-fluorophenyl                                                                 82-86                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.2 O4-methylsulphonylphenyl                                                            (oil)*                                    CF.sub.3                                                                            CN     (CH.sub.2).sub.2 SC.sub.6 H.sub.5                                                                   59-62                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.2 S3-methylsulphonylphenyl                                                           (oil)                                      CF.sub.3                                                                            CN     (CH.sub.2).sub.3 SC.sub.6 H.sub.5                                                                   (oil)                                      ______________________________________                                    

EXAMPLE 3

Aqueous 2N-sodium hydroxide solution (0.75 ml.) was added dropwise to astirred suspension of 3-hydroxy-3-p-methoxyphenylpropylisothiouroniumbromide (0.236 g.) and4-(4-cyano-3-trifluoromethylphenyl)-1,2-epoxy-2-trifluoromethylbut-trans-3-ene(0.205 g.) in tetrahydrofuran which was maintained at laboratorytemperature under an atmosphere of argon, and the mixture was stirred atlaboratory temperature for 20 hours and was then poured into saturatedaqueous ammonium chloride solution (30 ml.). The mixture was extractedthree times with diethyl ether (25 ml. each time) and the combinedextracts were washed with saturated aqueous sodium chloride solution (25ml.), dried over magnesium sulphate and evaporated to dryness. Themixture was purified by flash chromatography on a silica gel (Merck9385) column using a 40:1 v/v mixture of methylene chloride and ethylacetate as eluent. There was thus obtained, as an oil,4-(4-cyano-3-trifluoromethylphenyl)-1-(3-hydroxy-3-p-methoxyphenylpropyl)thio-2-trifluoromethylbut-trans-3-en-2-ol.

The process described above was repeated using the appropriateisothiouronium bromide (or chloride, indicated by an asterisk* in thetable) and the appropriate epoxide as starting materials, and there werethus obtained the compounds described in the following table:

    ______________________________________                                         ##STR22##                                                                    R.sup.9                 m.p. (°C.)                                     ______________________________________                                        (CH.sub.2).sub.3 OH     (oil)                                                 (CH.sub.2).sub.3 COCH.sub.3                                                                            (oil)*                                               (CH.sub.2).sub.3 COC.sub.6 H.sub.5                                                                    67-70                                                 (CH.sub.2).sub.3 CO2-thienyl                                                                           (oil)*                                               CH.sub.23-fluorophenyl  85-86                                                 (CH.sub.2).sub.34-methylthiophenyl                                                                     (oil)*                                               (CH.sub.2).sub.34-methylsulphonylphenyl                                                                (oil)*                                               (CH.sub.2).sub.34-methoxyphenyl                                                                       (oil)                                                 (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                                      66-69                                                 (CH.sub.2).sub.2 OC.sub.6 H.sub.5                                                                     83-85                                                 (CH.sub.2).sub.3 OC.sub.6 H.sub.5                                                                     63-65                                                 (CH.sub.2).sub.3 O4-methylthiophenyl                                                                   (oil)*                                               (CH.sub.2).sub.2 CHOH4-methylthiophenyl                                                               (oil)                                                 (CH.sub.2).sub.2 CHOH4-methylsulphonylphenyl                                                          (oil)                                                 (CH.sub.2).sub.3 CHOHC.sub.6 H.sub.5                                                                  (oil)                                                 CH.sub.2 CHCHC.sub.6 H.sub.5 (trans-)                                                                 130-132                                               ______________________________________                                    

There was also obtained by a similar process4-(3-chloro-4-cyanophenyl)-1-(4-methylsulphonylbenzyl)thio-2-trifluoromethylbut-trans-3-en-2-ol,using 4-methylsulphonylbenzylisothiouronium bromide as startingmaterial.

The isothiouronium salts used as starting materials in Examples 2 and 3were prepared by conventional means from thiourea and the appropriatealkyl halide or tosylate. Those which are novel and which werecharacterised by melting point are described in the following table:

    ______________________________________                                         ##STR23##                                                                    R.sup.9              X.sup.⊖                                                                        m.p. (°C.)                               ______________________________________                                        (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                                   Br       118-119                                         CH.sub.23-methylsulphonylphenyl                                                                    Cl       199-202                                         CH.sub.2(2-methylthiazol-4-yl)                                                                     Cl       168-170                                         CH.sub.2 CH(OCH.sub.3)CH.sub.2 OCH.sub.3                                                           tosylate 105-106                                         (CH.sub.2).sub.2 O4-methylsulphonylphenyl                                                          Br       165-167                                         (CH.sub.2).sub.3 COCH.sub.3                                                                        Cl       139-142                                         (CH.sub.2).sub.3 CO2-thienyl                                                                       Cl       112-114                                         (CH.sub.2).sub.34-methylthiophenyl                                                                 Cl       118-121                                         (CH.sub.2).sub.34-methylsulphonylphenyl                                                            Cl       161-166                                         (CH.sub.2).sub.3 O4-methylthiophenyl                                                               Cl       123-126                                         (CH.sub.2).sub.2 CHOH4-methylthiophenyl                                                            Br       188                                             ______________________________________                                    

EXAMPLE 4

A solution of potassium peroxymonosulphate (1.0 g.) in water (10 ml.)was added to a stirred solution of4-(3,4-dichlorophenyl)-1-[(2-methylthioethyl)thio]-2-trifluoromethylbut-trans-3-en-2-ol(Example 1; 0.1 g.) in methanol (10 ml.) and the mixture was stirred atlaboratory temperature for 16 hours, diluted with water (20 ml.) andextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium chloride solution, dried over magnesium sulphate andevaporated to dryness under reduced pressure, and the residue waspurified by chromatography on a silica gel column using a 1:1 v/vmixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate aseluant. There was thus obtained4-(3,4-dichlorophenyl)-1-[(2-methylsulphonylethyl)sulphonyl]-2-trifluoromethylbut-trans-3-en-2-ol,m.p. 187° C.

The process described above was repeated using the appropriatethio-compound described in Example 1 or 3 above as starting material,and there were thus obtained the compounds described in the followingtable:

    ______________________________________                                         ##STR24##                                                                    R.sup.3                                                                            R.sup.4                                                                              R.sup.10               m.p. (°C.)                          ______________________________________                                        Cl   Cl     (CH.sub.2).sub.2 OCH.sub.3                                                                           (oil)                                      Cl   Cl     (CH.sub.2).sub.3 OCH.sub.3                                                                           (oil)                                      CF.sub.3                                                                           CN     (CH.sub.2).sub.3 OCH.sub.3                                                                           (oil)                                      Cl   Cl     (CH.sub.2).sub.3 SO.sub.2 CH.sub.3                                                                   130                                        Cl   CN     (CH.sub.2).sub.3 SO.sub.2 CH.sub.3                                                                    90(d)                                     CF.sub.3                                                                           CN     (CH.sub.2).sub.3 SO.sub.2 CH.sub.3                                                                   140                                        Cl   Cl     CH.sub.2 C.sub.6 H.sub.5                                                                             (oil)                                      Cl   Cl     (CH.sub.2).sub.24-fluorophenyl                                                                       (oil)                                      CF.sub.3                                                                           CN     (CH.sub.2).sub.24-methylsulphonylphenyl                                                              (oil)                                      CF.sub.3                                                                           CN     (CH.sub.2).sub.2 SO.sub.2 C.sub.6 H.sub.5                                                            155-165                                    CF.sub.3                                                                           CN     (CH.sub.2).sub.2 SO.sub.23-methylsulphonylphenyl                                                      72-74                                     ______________________________________                                    

EXAMPLE 5

n-Butyl-lithium (1.2 ml. of a 1.6 molar solution in hexane) was addeddropwise to a stirred solution of(2-methoxyethoxy)methoxymethyl-tri-n-butylstannane (0.734 g., preparedby a similar process to that described in the Journal of the AmericanChemical Society, 1978, 100, 1483) in tetrahydrofuran (100 ml.) whichwas maintained at -78° C. under an atmosphere of argon. The mixture wasstirred at -78° C. for 15 minutes, a solution of1-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-ene-3-one (0.44 g.) intetrahydrofuran (10 ml.) was added dropwise and the mixture was stirredfor 2 hours at -78° C. Water (1 ml.) was added, the mixture was allowedto warm up to laboratory temperature and diethyl ether (20 ml.) wasadded. The mixture was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulphate and evaporated to dryness. Theresidue was purified by flash chromatography on a silica gel (Merck9385) column using a 1:1 v/v mixture of ethyl acetate and petroleumether (b.p. 60°-80° C.) as eluent. There was thus obtained as an oil1-(3,4-dichlorophenyl)-4-(2-methoxyethoxy)methoxy-3-trifluoromethylbut-trans-1-en-3-ol.

What we claim is:
 1. A compound of the formula ##STR25## wherein X hasthe formula ##STR26## or wherein ring A is phenyl or naphthyl; whereinR¹ is hydrogen, alkyl or alkanoyl each of up to 6 carbon atoms or aroylof up to 10 carbon atoms; wherein R², R³ and R⁴, which may be the sameor different, each is an electron withdrawing substituent selected fromhalogeno, nitro, cyano and trifluoromethyl, or each is hydrogen providedthat at least one of R², R³ and R⁴ is an electron-withdrawinggroup;wherein R⁵ and R⁶, which may be the same or different, each ishydrogen, halogeno or alkyl of up to 6 carbon atoms; wherein R⁷ is alkylor halogenoalkyl each of up to 6 carbon atoms; and wherein R⁸ has theformula

    --Y--Q--R.sup.9

wherein Y is straight- or branched-chain alkylene or alkenylene each ofup to 6 carbon atoms; wherein Q is --S--, --SO-- or SO₂ --; wherein R⁹is alkyl of up to 6 carbon atoms which contains one or more substituentsselected from halogeno, cyano, hydroxy, alkoxy of up to 6 carbon atoms,alkoxyalkoxy of up to 12 carbon atoms, and alkylenedioxy of 2 to 4carbon atoms wherein both oxygen atoms are attached to the same carbonatom of R⁹.
 2. A compound selected from the group consistingof1-(3-methoxypropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,1-(3-hydroxybutylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,1-(2-hydroxypropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,1-[3,3-(trimethylene-1,3-dioxy)propylthio]-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,and1-(3,3-ethylenedioxybutylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol.3. A compound selected from the group consisting of1-(3-hydroxypropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,1-(2,3-dihydroxypropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol,and1-(2,3-dimethoxypropylthio)-4-(4-cyano-3-trifluoromethylphenyl)-2-trifluoromethylbut-trans-3-en-2-ol.4. A compound as claimed in claim 1 wherein X is --CR⁵ ═CR⁶ --, in thetrans-configuration, wherein ring A is phenyl, wherein one or two (thesame or different) of R², R³ and R⁴ are fluoro, chloro, cyano,trifluoromethyl or nitro, the others of R², R³ and R⁴ being hydrogen,wherein R¹, R⁵ and R⁶ are all hydrogen, wherein R₇ is trifluoromethyl,pentafluoroethyl, heptafluoropropyl, chloromethyl or dichloromethyl;wherein Q is --S, --SO-- or --SO₂, wherein Y is --CH₂ -- and wherein R⁹is straight-chain-alkyl of up to 4 carbon atoms which bears one or twosubstituents selected from chloro, cyano, hydroxy, methoxy and ethoxy,or which bears one such substituent and also three fluorine substituentson the terminal carbon atom; or which bears an ethylenedioxy ortrimethylene-1,3-dioxy substituent; or which bears three fluorinesubstituents on the terminal carbon atom.
 5. The compound1-(3-methoxypropylthio)-4-(3-chloro-4-cyanophenyl)-2trifluoromethylbut-trans-3-en-2-ol.6. A compound according to claim 1 wherein R⁹ is alkyl of up to 6 carbonatoms which contains one or more substituents selected from: halogeno,hydroxy, alkoxy, of up to 6 carbon atoms, alkoxyalkoxy of up to 12carbon atoms, and alkylenedioxy of up to 2 to 4 carbon atoms whereinboth oxygen atoms are attached to the same carbon atom of R⁹.
 7. Acompound according to claim 6 wherein R⁹ is straight-chain-alkyl of upto 4 carbon atoms which bears one or two substituents selected fromchloro, hydroxy, methoxy, ethoxy, or which bears one such substituentand also three fluorine substituents on the terminal carbon atom; orwhich bears an ethylenedioxy or trimethylene-1,3dioxy substituent; orwhich bears three fluorine substituents on the terminal carbon atom. 8.A compound as claimed in claim 4 wherein ring A is 3,4-dichlorophenyl,3-chloro-4-cyanophenyl, 4-cyano-3-trifluoromethylphenyl or 4-fluoro-3-trifluoromethylphenyl and wherein R⁷ is trifluoromethyl.
 9. Apharmaceutical or veterinary composition having antiandrogenicproperties which comprises an effective amount of a compound as claimedin claim 1 in association with a pharmaceutically-acceptable diluent orcarrier.
 10. A method for producing an antiandrogenic effect in awarm-blooded animal which comprises administering to said animal aneffective amount of a compound claimed in claim 1.